New Antioxidants and their quinoid metabolites

Oxygen radicals are involved in the pathogenesis of numerous diseases. However, intervention trials involving supplementation of antioxidants to healthy man and animals were only partially successful. This might be due to physiological activities of their respective antioxidant metabolites, which may counteract the beneficial effects of antioxidants. The major metabolite of the antioxidant vitamin E is tocopheryl quinone (TQ). It is well known, that quinoid compounds in contact with redox-enzymes can exert prooxidative activity , e.g. by stimulating oxygen radical formation, as well as antioxidant activity in its reduced form. Due to the high redox activity and appropriate binding sites for quinones in mitochondria the interference of TQ in the mitochondrial electron transfer and oxygen radical formation can be expected. We hypothesize that the efficiency of vitamin E-type antioxidants can be increased by avoiding the formation of quinoid metabolites from chromanoxyl radical intermediates. This could be achieved by employing novel vitamin E-derivatives, which form more stable chromanoxyl radicals. In contrast, the metabolic conversion of the vitamin E-type antioxidant ubichromenol to ubiquinone could be employed to deliver ubiquinone to mitochondria, which is known to improve the mitochondrial energy conservation. These approaches will point out new ways to increase the benefits of antioxidant supplementation, and will improve the understanding of its effects and influencing factors.

The intake of food supplements besides the normal food is widespread in the population of North America and gets also more and more accepted in Europe. Also for animal feed such additives play an increasing role, because the use of other supporting ingredients, such as antibiotics, is more and more restricted. A class of substances which are often included in such preparations, are vitamins of the E type, the so-called tocopherols. Although it is known for a long time that these lipid-soluble substances act as scavengers of free radicals in the organism, in particular in clinical studies the benefit of vitamin E for the prevention of radical-induced cardiovascular diseases was not unequivocally shown. Indeed, many research groups focused their interest on the vitamin E even without consideration of possible toxicological consequences arising form oxidation products which originate necessarily from the protective action of vitamin E. The finished project dealt with chromanols (the basic structure of vitamin E compounds) and their oxidation products the quinones (compounds such as ubiquinone (Coenzyme Q10)). In this study, the suitability of new chromanols as radical scavengers was examined by physico-chemical methods. Furthermore, the biological activity of these compounds and their oxidation products was tested in mitochondria, which are the power stations of the cells. The new twin-chromanol turned out to be more protective in the chemical system as well as in mitochondria than vitamin to E analogues. The oxidation product of vitamin E, tocopheryl quinone, has a structure similar to ubiquinone, which plays an important role as electron carrier in the mitochondria. Indeed, our experiments demonstrated that tocopheryl quinone partially inhibits the mitochondrial electron transfer and could possibly impair the energy supply of the cell. However, a supposed physiological function of tocopheryl quinone in the outer mitochondrial membrane could not be confirmed. On account of the structural similarity of tocopheryl quinone and ubiquinone the possibility to prepare vitamin E-like compounds from ubiquinone was examined. The obtained ubichromanol (a molecular combination of vitamin E and ubiquinone) has similar radical-scavenging properties like vitamin E itself. The oxidation products of ubichromanol, which are very similar to the natural ubiquinone inhibit the mitochondrial function of ubiquinone by far less than tocopheryl quinone. Therefore, the consideration of chromanols together with their quinoid oxidation products offers new possibilities for the understanding of the vitamin E function and the development of new ubiquinone-based antioxidants.